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Cisplatin is an anticancer drug that can be used to treat a variety of solid tumors, where clinical use may be affected by several factors, including dose-limiting side effects and the emergence of drug resistance. Micellar-forming polymeric conjugates are a type of polymeric nanocarrier that can preferentially accumulate in tumors, thereby increasing therapeutic efficacy. In the current study, carboxylated PiPOx was synthesized first using a click reaction of 2-isopropenyl 2-oxazoline (iPOx) with thioglycolic acid (TGA) or methyl thioglycolate, followed by methyl triflate-initiated cationic ring opening polymerization (CROP). Next, different strategies were employed to prepare carboxylated PiPOx-mPEG copolymers: (a) CROP was initiated by iPOx-modified mPEG-thiol, (b) TGA-modified PiPOx were end-capped with mPEG-NH2, or (c) TGA-modified iPOx and iPOx-modified mPEG-thiol were randomly copolymerized. 1H-NMR, FT-IR, SEC, and potentiometric titration methods were used to characterize the synthesized polymers. Cisplatin-polymer conjugation was performed at three ratios of drug-to-polymer carboxyl groups (0.25, 0.5, and 1), and the conjugated cisplatin content was determined using UV–vis spectroscopy at 705 nm with O-phenylenediamine reagent. The cisplatin loading efficiencies (%) were 59.3, 26.7, and 91.0 for the respective copolymers at the chosen cisplatin/carboxyl 1:1 mol ratio. Cisplatin-conjugated PiPOx(TGA)-b-mPEG and mPEG-g-PiPOx(TGA) had mean hydrodynamic sizes of 113.3 and 178.8 nm, respectively. TEM imaging confirmed the formation of discrete and spherical particles of the cisplatin-conjugated copolymer. The MTT cytotoxicity assay demonstrated higher cytotoxicity of PiPOx(TGA)-b-mPEG compared to PiPOx(TGA)-g-mPEG polymers in both sensitive and resistant ovarian cancer cells. The IC50 values were approximately 113 µg/ml for PiPOx(TGA)-b-mPEG and 232 µg/ml for PiPOx(TGA)-g-mPEG in resistant tumor cells, confirming the potential application of cisplatin-conjugated copolymers in cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Leishmaniasis is a parasitic disease caused by the Leishmania protozoan affecting millions of people worldwide, especially in tropical and subtropical regions. The immune response involves the activation of various cells to eliminate the infection. Understanding the complex interplay between Leishmania and the host immune system is crucial for developing effective treatments against this disease. Methods: This study collected extensive transcriptomic data from macrophages, dendritic, and NK cells exposed to Leishmania spp. Our objective was to determine the Leishmania-responsive genes in immune system cells by applying meta-analysis and feature selection algorithms, followed by co-expression analysis. Results: As a result of meta-analysis, we discovered 703 differentially expressed genes (DEGs), primarily associated with the immune system and cellular metabolic processes. In addition, we have substantiated the significance of transcription factor families, such as bZIP and C2H2 ZF, in response to Leishmania infection. Furthermore, the feature selection techniques revealed the potential of two genes, namely G0S2 and CXCL8, as biomarkers and therapeutic targets for Leishmania infection. Lastly, our co-expression analysis has unveiled seven hub genes, including PFKFB3, DIAPH1, BSG, BIRC3, GOT2, EIF3H, and ATF3, chiefly related to signaling pathways. Conclusions: These findings provide valuable insights into the molecular mechanisms underlying the response of immune system cells to Leishmania infection and offer novel potential targets for the therapeutic goals. Author summary: Leishmaniasis is a group of diseases caused by protozoan parasites belonging to the genus Leishmania. The infection involves various cells, and effective diagnosis and treatment require a clear understanding of its multiple aspects. We conducted a study using meta-analysis and feature selection algorithms combined with co-expression analysis to shed light on the key responsive genes and mechanisms involved in Leishmania infection. Our findings revealed transcriptional signatures associated with essential cellular metabolic functions and immune system response. We also confirmed the critical role of transcription factor families, including bZIP and C2H2 ZF, in response to Leishmania infection. The applied feature selection techniques identified two genes that show potential as Leishmania infection biomarkers and treatment targets. Moreover, our co-expression analysis identified seven crucial hub genes in signaling pathways. These findings provide valuable insights into the molecular mechanisms underlying the immune system cells' response to Leishmania infection and present novel potential targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

[Display omitted] • The VHH displaying phage fabricated for VEGF detection. • The preparation and operation simplified by labeling steps elimination. • The results revealed excellent specificity and reliability of proposed immunosensor. • Analysis of results showed valuable LOD, LOQ and wide linear range. Herein the pioneering label-free electrochemistry-based immunosensor with exceptional sensitivity for the rapid and efficient detection of vascular endothelial growth factor (VEGF) was precisely designed based on the phage display technique. The specific variable domain of a heavy-chain antibody (VHH)-displaying phage against VEGF 8–109 was successfully immobilized on Au nanoparticles deposited gold electrode modified by 3-mercapto propionic acid and 11-mercaptoundecanoic acid and then, carbodiimide coupling reaction using N-hydroxysuccinimide and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. Electrochemical characterizations of the proposed immunosensor were performed by PM-FT-IRRAS, scanning electron microscopy, cyclic voltammetry and electrochemical impedance spectroscopy techniques. Electrochemical measurements were performed using differential pulse voltammetry in phosphate buffer containing [Fe(CN) 6 ]3–/4– ions as a probe, where the decline in the peak current value was related to a concentration of the antigen cast on the surface of the immunosensor. Under the optimum conditions (pH 7.4, interval time 20 s, and step potential 0.1 V), a linear range of response for the detection of VEGF 8–109 by immunosensor was 0.03–10,000 pg/mL (in log concentration), with a limit of detection of 11 fg/mL. The specificity of the immunosensor was also investigated against some typical blood growth factors. The novel immunosensor was applied to evaluate VEGF levels in human serum specimens clinically. The recommended immunosensor was uncomplicated, reasonably priced, and showed adequate accuracy and specificity, which could be applied in the early diagnosis of tumors. [ABSTRACT FROM AUTHOR]

Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies. This study summarizes the clinical, imaging, and molecular data of these patients for five years. The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1 , and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis. The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042). [ABSTRACT FROM AUTHOR]

The design and synthesis of novel cytotoxic agents is still an interesting topic for medicinal chemistry researchers due to the unwanted side effects of anticancer drugs. In this study, a novel series of uracil–azole hybrids were designed and synthesized. The cytotoxic activity, along with computational studies: molecular docking, molecular dynamic simulation, density functional theory, and ADME properties were also, evaluated. The compounds were synthesized by using 3-methyl-6-chlorouracil as the starting material. Cytotoxicity was determined using MTT assay in the breast carcinoma cell line (MCF-7) and Hepatocellular carcinoma cell line (HEPG-2). These derivatives demonstrated powerful inhibitory activity against breast and hepatocellular carcinoma cell lines in comparison to Cisplatin as positive control. Among these compounds, 4j displayed the best selectivity profile and good activity with IC50 values of 16.18 ± 1.02 and 7.56 ± 5.28 µM against MCF-7 and HEPG-2 cell lines respectively. Structure–activity relationships revealed that the variation in the cytotoxic potency of the synthesized compounds was affected by various substitutions of benzyl moiety. The docking output showed that 4j bind well in the active site of EGFR and formed a stable complex with the EGFR protein. DFT was used to investigate the reactivity descriptors of 4a and 4j. The outputs demonstrated that these uracil–azole hybrids can be considered as potential cytotoxic agents. [ABSTRACT FROM AUTHOR]

• A new set of imidazole derivatives were synthesized and characterized. • The synthesized compounds (7a-f) were screened for their in vitro antifungal activities against several fungal strains. • Compounds 7c, 7d and 7f exhibited excellent activities against tested fungi species with MIC 90 values in the range of 0.5-16 µg/ml. • Molecular modelling studies and molecular dynamic simulation were carried out to predict the possible interaction mode of these compounds in the binding site of lanosterol 14α-demethylase (CYP51). • These compounds can be considered as antifungal candidates for further development. Fungal infections have become a serious threat to human health due to their high incidence and mortality. In this study, a new set of imidazole derivatives (7a-f) were synthesized and their chemical structures were characterized using spectroscopic techniques including IR, 1H-NMR, 13C-NMR and Mass. In the following, the antifungal activities of these derivatives were evaluated against several yeasts, aspergillus and dermatophyte species using the CLSI method. In addition, to check the safety of the synthesized compounds, the in vitro cytotoxicity activity of these compounds was investigated towards normal human fibroblasts cell line (MRC-5) using MTT assay. The obtained biological results indicated that these compounds acted as the most potential antifungal agents. In particular, compounds 7c, 7d and 7f exhibited excellent activity against Candida albicans, Candida tropicalis, Candida glabrata, Candida krusei, Candida dubliniensis, Candida parapsilosis , and Cryptococcus neoformans species with MIC 50 values in the range of 0.5-16 µg/ml. The cytotoxicity results showed that these compounds have low toxicity against normal human fibroblasts cell line (MRC-5). Additionally, molecular modelling studies and molecular dynamic simulation were carried out to predict the binding energy and possible interaction mode of these compounds in the binding site of lanosterol 14α-demethylase (CYP51) as a conventional target for azole derivatives. In silico ADME study was also performed to investigate the physicochemical features of the synthesized imidazole derivatives. According to the results, these compounds can be considered as promising antifungal candidates for further development. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of imidazole bearing different substituted thioquinolines were synthesized as α-glucosidase inhibitors. • All derivatives exhibited significantly better potency (IC 50 = 12.1 ± 0.2 to 102.1 ± 4.9 µM) compared to the standard drug acarbose. • In vivo studies showed that 8g did not cause acute toxicity at 2000 mg/kg doses. • 8g reduced fasting blood glucose levels and decreased blood glucose levels following sucrose loading compared to acarbose. Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood sugar levels. It was shown that modulating the activity of α-glucosidase, an enzyme involved in carbohydrate digestion and absorption, can improve blood sugar control and overall metabolic health in individuals with T2DM. As a result, in the current study, a series of imidazole bearing different substituted thioquinolines were designed and synthesized as α-glucosidase inhibitors. All derivatives exhibited significantly better potency (IC 50 = 12.1 ± 0.2 to 102.1 ± 4.9 µM) compared to the standard drug acarbose (IC 50 = 750.0 ± 5.0 µM). 8g as the most potent analog, indicating a competitive inhibition with K i = 9.66 µM. Also, the most potent derivative was subjected to molecular docking and molecular dynamic simulation against α-glucosidase to determine its mode of action in the enzyme and study the complex's behavior over time. In vivo studies showed that 8g did not cause acute toxicity at 2000 mg/kg doses. Additionally, in a diabetic rat model, treatment with 8g significantly reduced fasting blood glucose levels and decreased blood glucose levels following sucrose loading compared to acarbose, a standard drug used for blood sugar control. The findings suggest that the synthesized compound 8g holds promise as an α-glucosidase inhibitor for improving blood sugar control and metabolic health. [ABSTRACT FROM AUTHOR]